ABSTRACT: Cigarette smoke is one of the most prevalent developmental toxins. The World Health Organization estimates that ~700 million children worldwide are exposed either pre- and/or postnatally to cigarette smoke. The overarching theme of this proposal is to study the role of developmental cigarette smoke exposure on the colonization, maintenance, and function of the gut microbiome. Since neonatal gut colonization is initiated by exposure to maternal bacteria during birth, and tobacco smoke exposure alters cecal bacterial content in adults, we propose that maternal tobacco smoke exposure during pregnancy results in aberrant bacterial colonization of the neonatal gut such that pathogenic bacterial overgrowth occurs, and that continued cigarette smoke exposure during postnatal development entrenches this phenotype. Utilizing a unique and well characterized murine inhalation model simulating maternal cigarette smoking during pregnancy, and newborn smoke exposure - established in our laboratory - we will: 1) Examine the impact of developmental cigarette smoke exposure on offspring gut microbial community colonization and the persistence of the microbiome phenotype; 2) Examine the impact of developmental cigarette smoke exposure on offspring gut microbial community function; and 3) Compare the outcomes within our murine model of developmental tobacco cigarette smoke exposure with findings from very low birth weight human infants of mothers who smoked during pregnancy. Central Hypothesis: Developmental cigarette smoke exposure induces pathogenic intestinal bacterial colonization with persistent alterations in carbohydrate metabolism in mice, with a similar impact in very low birth weight infants of mothers who smoked during pregnancy.